Stable solid preparation containing 4,5-epoxymorphinan derivative

ABSTRACT

It is an object of the present invention to provide a stable solid preparation comprising a 4,5-epoxymorphinan derivative or a pharmacologically acceptable acid addition salt thereof as an effective ingredient. 
     That is, the present invention provides the stable solid preparation comprising the 4,5-epoxymorphinan derivative or the pharmacologically acceptable acid addition salt thereof as the effective ingredient, and comprising sodium thiosulfate, a sugar or a sugar alcohol and hydroxypropylcellulose having a low degree of substitution in an amount of 1 to 30% by weight per weight of a unit containing the effective ingredient.

TECHNICAL FIELD

The present invention relates to a stable solid preparation comprising a4,5-epoxymorphinan derivative or a pharmacologically acceptable acidaddition salt thereof. More particularly, the present invention relatesto a stable solid preparation containing a 4,5-epoxymorphinan derivativeor a pharmacologically acceptable acid addition salt thereof as aneffective ingredient; sodium thiosulfate, a sugar or a sugar alcohol;and hydroxypropylcellulose having a low degree of substitution in anamount of 1 to 30% by weight per weight of a unit containing theeffective ingredient.

The unit containing the effective ingredient here indicates a unit of asolid ingredient being directly contacted with the effective ingredientin the preparation, and for example, is a core tablet in the case of afilm-coating tablet, a filled solid ingredient in which a drug issupported and dispersed in the case of a capsule and a core granule inthe case of a granule coated with a functional film, which refers to anessential portion that governs a stability of the drug.

BACKGROUND ART

The 4,5-epoxymorphinan derivative represented by the general formula (I)or the pharmacologically acceptable acid addition salt thereof that isthe effective ingredient of the present invention has a remarkableantipruritic effect, and has been disclosed as an effective compound fora drug of treating pruritus in various diseases associated with thepruritus (e.g., see patent Document 1 [U.S. Pat. No. 3,531,170]).However, it has been known that the 4,5-epoxymorphinan derivative ischemically unstable to light, heat and oxygen (e.g., see Patent Document2 [International Publication WO99/02158 Pamphlet]). Therefore, it hasbeen necessary to develop a preparation having the good stability inorder to assure its quality.

Conventionally, as methods for stabilizing various morphinan compoundsincluding morphine, a technique of adding a basic ingredient to morphine(e.g., see Patent Document 3 [JP Hei-2-160719-A]), methods of combiningan antioxidant such as sodium thiosulfate and tocopherol with naloxone(e.g., Patent Document 4 [International Publication WO98/35679Pamphlet]), methods of adding a chelating agent and a citrate buffer tomethylnaltrexone (e.g., see Patent Document 5 [JP 2006-522818]) andmethods of blending an organic acid and a chelate forming agent tonaltrexone hydrochloride (e.g., see Patent Document 6 [JP 2005-531515])have been disclosed. However, these reports do not describe astabilization effect of hydroxypropylcellulose having a low degree ofsubstitution, which is a particular disintegrant, and it does notnecessarily perform such an effect. The technique of stabilizing the4,5-epoxymarphinan derivative has been disclosed in detail in PatentDocument 2, and it has been described that a stable pharmaceuticalcomposition is obtained by containing sugars or sugar alcohols, anantioxidant such as sodium thiosulfate, or the like. However, nothing isdescribed for types and blended amounts of disintegrants and bindersthat are effective for the stabilization; thus, the stabilization effectgiven to a solid preparation by hydroxypropylcellulose having the lowdegree of substitution, which is the particular disintegrant, has notbeen revealed.

Meanwhile, an orally disintegrating tablet that can be taken withoutwater, which aims at improving a dosing compliance, has been disclosedas the solid preparation containing sugars or sugar alcohols such aslactose, mannitol or erythritol and containing hydroxypropylcellulosehaving the low degree of substitution as the disintegrant. The followinghave been disclosed: a composition that contains the effectiveingredient, the sugar alcohols and hydroxypropylcellulose having the lowdegree of substitution, having the degree of substitution and a bulkdensity of a particular hydroxypropoxyl group and enhances adisintegrating property (e.g., see Patent Document 7 [JPHei-11-43429-A], Patent Document 8 [JP 2001-328948-A]); or an externallubricant tableting method in which the amount of added magnesiumstearate is minimized in order to shorten a disintegrating time in anoral cavity (e.g., see Patent Document 9 [International PublicationWO2003/103713 Pamphlet]); the technique that defines an ethanolpermeation speed in a lubricant (e.g., see Patent Document 10[International Publication WO2001/076565 Pamphlet]). However, the solidpreparation of the present invention need not be disintegrated in theoral cavity, and thus is essentially different from these problems. Moreimportantly, these reports do not describe sodium thiosulfate, and do nodescribe its effect on stabilization; therefore, the present inventioncan not be conceived easily from these reports.

Meanwhile, a technique of preventing degradation of the drug orfunctional change of functional particles due to compression by usingspray dry powders containing the sugar alcohol has been disclosed (e.g.,see Patent Document 11 [International Publication WO2002/070013Pamphlet).

However, in the above report, sodium thiosulfate is not described, andthe stabilization effect given to a storage stability of the drug byaddition of the sugar alcohol or sodium thiosulfate is not described atall.

-   Patent Document 1: U.S. Pat. No. 3,531,170-   Patent Document 2: International Publication WO99/02158 Pamphlet-   Patent Document 3: JP Hei-2-160719-A-   Patent Document 4: International Publication WO98/35679 Pamphlet-   Patent Document 5: JP 2006-522818-   Patent Document 6: JP 2005-531515-   Patent Document 7: JP Hei-11-43429-A-   Patent Document 8: JP 2001-328948-A-   Patent Document 9: International Publication WO2003/103713 Pamphlet-   Patent Document 10: International Publication WO2001/076565 Pamphlet-   Patent Document 11: International Publication WO2002/070013 Pamphlet

DISCLOSURE OF INVENTION Problem to be Solved by the Invention

It is an object of the present invention to provide a stable solidpreparation comprising a 4,5-epoxymorphinan derivative or apharmacologically acceptable acid addition salt thereof as an effectiveingredient.

Means for Solving the Problem

It was studied to formulate the 4,5-epoxymorphinan derivativerepresented by the general formula (I) or the pharmacologicallyacceptable acid addition salt thereof into a solid preparation. As aresult, although the method for stabilization by adding an antioxidantsuch as sodium thiosulfate known conventionally (e.g., see PatentDocument 2) was demonstrated to be effective for the stabilization ofthe effective ingredient in a liquid state, when this method wasutilized for the solid preparation, it was found to be difficult tominimize degrading and keep the stability sufficient as the solidpreparation in an unpacked state or an ordinary packed state over a longperiod of time.

Thus, the present inventors have studied extensively to develop thestable solid preparation comprising the 4,5-epoxymorphinan derivativerepresented by the general formula (I) or the pharmacologicallyacceptable acid addition salt thereof, and have obtained a finding thatthe remarkable stabilization effect is obtained by making the4,5-epoxymorphinan derivative coexist with sodium thiosulfate, a sugaror a sugar alcohol. On the other hand, it has been found thatdegradation is facilitated by adding, for example, a binder such aspolyvinyl alcohol or hydroxypropylcellulose, or a disintegrant such ascroscarmellose sodium or carmellose sodium, generally used informulation. However, the present inventors have found surprisingly thatonly hydroxypropylcellulose having the low degree of substitution amongthe disintegrants allows the 4,5-epoxymorphinan derivative or thepharmacologically acceptable acid addition salt thereof to exist stablyin the solid preparation by making it coexist with sodium thiosulfate,the sugar or the sugar alcohol, and then have completed the presentinvention.

Accordingly, the present invention is related to the invention describedbelow.

(1) A stable solid preparation comprising as an effective ingredient a4,5-epoxymorphinan derivative represented by the general formula (I) ora pharmacologically acceptable acid addition salt thereof, andcomprising sodium thiosulfate, a sugar or a sugar alcohol, andhydroxypropylcellulose having a low degree of substitution in an amountof 1 to 30% by weight per weight of a unit containing the effectiveingredient.(2) The stable solid preparation according to (1), wherein said sugar orsugar alcohol contains at least one selected from the group consistingof starch, saccharose, lactose, mannitol, erythritol and maltitol.(3) The stable solid preparation according to any of (1) or (2), whereinsaid sugar or sugar alcohol is a granulated granule manufactured byextruding granulation, agitating granulation, spray drying or fluidizedbed granulation.(4) The stable solid preparation according to any of (1) to (3), whichis obtained by a production method comprising a step of dissolving orsuspending the effective ingredient in water or a pharmacologicallyacceptable solvent and adding to the sugar or the sugar alcohol.(5) The stable solid preparation according to any of (1) to (4), whichis a tablet, a capsule; a granule, a subtle granule or a powder.(6) A stable solid preparation, wherein the solid preparation accordingto any of (1) to (5) is coated.

Effect of the Invention

The solid preparation comprising the 4,5-epoxymorphinan derivativerepresented by the general formula (I) or the pharmacologicallyacceptable acid addition salt thereof as the effective ingredient isexcellent in storage property and stably contains the effectiveingredient even after a long period of time has passed since itsproduction.

BEST MODES FOR CARRYING OUT THE INVENTION

The solid preparation of the present invention is described below.

A 4,5-epoxymorphinan derivative which is the effective ingredient of thepresent invention is a compound represented by the general formula (I)or the pharmacologically acceptable acid addition salt thereof.

Here, in the formula (I), a double line of a dashed line and a solidline represents a double bond or a single bond; R¹ represents alkylhaving 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbonatoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbonatoms, allyl, furan-2-ylalkyl having 1 to 5 carbon atoms orthiophene-2-ylalkyl having 1 to 5 carbon atoms; R² represents hydrogen,hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1to 5 carbon atoms, alkyl having 1 to 5 carbon atoms or —NR⁷R⁸; R⁷represents hydrogen or alkyl having 1 to 5 carbon atoms; R⁸ representshydrogen, alkyl having 1 to 5 carbon atoms or —C(═O)R⁹—; R⁹ representshydrogen, phenyl or alkyl having 1 to 5 carbon atoms; R³ representshydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms or alkoxyhaving 1 to 5 carbon atoms; A represents —N(R⁴)C(═X)—, —N(R⁴)C(═X)Y—,—N(R⁴)—, or —N(R⁴)SO₂— (wherein X and Y each independently representNR⁴, S or O, and R⁴ represents hydrogen, straight or branched alkylhaving 1 to 5 carbon atoms or aryl having 6 to 12 carbon atoms, and R⁴in the formula may be the same or different); B represents a valencebond, straight or branched alkylene having 1 to 14 carbon atoms (withthe proviso that the alkylene may be substituted with at least one ormore substituents selected from the group consisting of alkoxy having 1to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy,fluorine, chlorine, bromine, iodine, amino, nitro, cyano,trifluoromethyl, trifluoromethoxy and phenoxy, and wherein 1 to 3methylene groups may be replaced with carbonyl groups), straight orbranched non-cyclic unsaturated hydrocarbon containing 1 to 3 doublebonds and/or triple bonds and having 2 to 14 carbon atoms (with theproviso that the hydrocarbon may be substituted with at least one ormore substituents selected from the group consisting of alkoxy having 1to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy,fluorine, chlorine, bromine, iodine, amino, nitro, cyano,trifluoromethyl, trifluoromethoxy and phenoxy, and wherein 1 to 3methylene groups may be replaced with carbonyl groups), or straight orbranched saturated or unsaturated hydrocarbon containing 1 to 5thioether bonds, ether bonds and/or amino bonds and having 1 to 14carbon atoms (with the proviso that the heteroatom is not directly boundto A, and 1 to 3 methylene groups may be replaced with carbonyl groups);R⁵ represents hydrogen or an organic group having the following basicskeleton:

(with the proviso that the organic group may be substituted with atleast one or more substituents selected from the group consisting ofalkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms,alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine,bromine, iodine, amino, nitro, cyano, isothiocyanate, trifluoromethyl,trifluoromethoxy and methylenedioxy); and R⁶ represents hydrogen, alkylhaving 1 to 5 carbon atoms or alkanoyl having 1 to 5 carbon atoms.

The double line of the dashed line and solid line in the general formula(I) represents the double bond or the single bond as described above,but preferably represents the single bond.

In the general formula (I), R¹ is preferably methyl, ethyl, propyl,butyl, isobutyl, cyclopropylmethyl, allyl, benzyl or phenethyl, and morepreferably cyclopropylmethyl or allyl.

R² and R³ are each independently preferably hydrogen, hydroxy, acetoxyor methoxy.

A is preferably —N(R⁴)C(═O)—, —N(R⁴)C(═O)O—, —N(R⁴)— or —N(R⁴)SO₂— (R⁴represents hydrogen, or straight or branched alkyl having 1 to 5 carbonatoms), and among them —N(R⁴)C(═O)— or —N(R⁴)C(═O)O— (R⁴ representshydrogen, or straight or branched alkyl having 1 to 5 carbon atoms) ispreferable.

B is preferably straight alkylene having 1 to 3 carbon atoms, —CH═CH—,—C≡C—, —CH₂O— or —CH₂S—, and among them straight alkylene having 1 to 3carbon atoms, —CH═CH— or —C≡C— is preferable.

R⁵ is preferably hydrogen or the organic group having the followingbasic skeleton:

(with the proviso that the organic group may be substituted with atleast one or more substituents selected from the group consisting ofalkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms,alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine,bromine, iodine, amino, nitro, cyano, isothiocyanate, trifluoromethyl,trifluoromethoxy and methylenedioxy).

R⁶ is preferably hydrogen.

The pharmacologically preferable acid addition salt may includeinorganic salts such as hydrochloride salts, sulfate salts, nitratesalts, hydrobromide salts, hydroiodide salts and phosphate salts;organic carboxylate salts such as acetate salts, lactate salts, citratesalts, oxalate salts, glutarate salts, malate salts, tartrate salts,fumarate salts, mandelate salts, maleate salts, benzoate salts andphthalate salts; and organic sulfonate salts such as methanesulfonatesalts, ethanesulfonate salts, benzenesulfonate salts, p-toluenesulfonatesalts and camphorsulfonate salts. Among them, hydrochloride salts,hydrobromide salts, phosphate salts, tartrate salts, maleate salts andmethanesulfonate salts are preferable, but certainly the salts are notlimited thereto.

As the 4,5-epoxymorphinan derivative represented by the general formula(I) or the pharmacologically acceptable acid addition salt thereof inthe present invention, particularly preferable are17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinanhydrochloride (hereinafter referred to as Compound 1) and17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinanhydrochloride (hereinafter referred to as Compound 2).

The 4,5-epoxymorphinan derivative or the pharmacologically acceptableacid addition salt thereof that is a medical ingredient of the solidpreparation of the present invention can be produced, for example, bythe method described in U.S. Pat. No. 2,525,552.

A blended amount of the 4,5-epoxymorphinan derivative or thepharmacologically acceptable acid addition salt thereof that is themedical ingredient of the solid preparation of the present invention isnot particularly limited as long as a therapeutic effect is exerted.

For example, it can be in the range of 0.01 to 10,000 μg/preparation,and ordinarily the range of 0.1 to 1,000 μg/preparation is preferable.

As sodium thiosulfate used in the present invention, those generallycommercially available may be used. Sodium thiosulfate may be ananhydride or a hydrate (pentahydrate), but is preferably the hydrate.Its blended amount may be 5% by weight or less per weight of a unitcontaining the effective ingredient, and is preferably 0.5% by weight orless per weight of a unit containing the effective ingredient. A lowerlimit of the blended amount is not particularly limited, and isordinarily 0.00001% by weight or more per weight of a unit containingthe effective ingredient. In the present invention, percent by weightper weight of a unit containing the effective ingredient means apercentage of the weight to the weight of a solid ingredient unit beingdirectly contacted with the effective ingredient in the preparation.

As the sugar or the sugar alcohol used in the present invention, thosegenerally Commercially available may be used. Examples of the sugar orsugar alcohol include starch, saccharose, lactose, mannitol, erythritoland maltitol, and preferably include mannitol. These specific examplescan be used alone or in combination of two or more. The blended amountis not particularly limited, and is ordinarily 65% by weight or more,may be 70% by weight or more, is preferably 75% by weight or more andmore preferably 80% by weight or more based on weight of a unitcontaining the effective ingredient in the preparation. A particle formof the sugar or sugar alcohol is not particularly limited, and is agranulated granule, powder, fine powder or the like. For example, whenthe solid preparation of the present invention is formulated into thetablet, the granulated granule is preferable in terms of handling. Asthe granulated granule, those produced by the known technique such as aspray drying, an extruding granulation, an agitating granulation or afluidized bed granulation can be used. More preferably, a high tablethardness is achieved without causing tableting trouble by using thespray dried granule. When a particle diameter of the sugar or sugaralcohol is small, the tableting trouble easily occurs and high tablethardness is hardly achieved. Thus, an average particle diameter whenmeasured according to a particle size measurement method in the 15threvised Japanese Pharmacopoeia may be 10 μm or more, is preferably 50 μmor more and more preferably 80 μm or more. An upper limit of theparticle diameter is ordinarily 3,000 μm or less. The amount of thesugar or sugar alcohol to be blended in the solid preparation of thepresent invention can be ordinarily 65 to 99% by weight, 70 to 99% byweight, preferably 75 to 99% by weight and more preferably 80 to 99% byweight per weight of a unit containing the effective ingredient.

As hydroxypropylcellulose having the low degree of substitution used inthe present invention, those generally commercially available may beused. The blended amount thereof may be 1 to 30% by weight per weight ofa unit containing the effective ingredient. The average particlediameter of hydroxypropylcellulose having the low degree of substitutionis preferably 10 to 300 μm and more preferably 30 to 200 μm. As a bulkdensity of hydroxypropylcellulose having the low degree of substitution,a loose bulk density is preferably less than 0.40 g/ml, and the lowerlimit thereof is generally 0.10 g/ml or more. Meanwhile, a content ofhydroxypropoxyl group is preferably 10.0% by weight to 12.9% by weight.The above loose bulk density means the bulk density in the state offilling thinly, and is measured by supplying a sample into a cylindricalcontainer (material: stainless) having a diameter of 5.03 cm and aheight of 5.03 cm (volume of 100 ml) through a JIS sieve with 24 meshfrom above (23 cm), flattening an upper surface and weighing thecontainer.

Pharmacologically acceptable additives such as lubricants and coloringagents in addition to the above ingredients may be added if necessary tothe solid preparation of the present invention. The lubricant include,for example, magnesium stearate, calcium stearate, talc, stearic acid,sucrose fatty acid ester and light silic anhydride.

Pharmaceutically acceptable disintegrants or binders in addition to theabove ingredients may be added if necessary to the solid preparation ofthe present invention. For example, crystalline cellulose,hydroxypropylcellulose, partially pregelatinized starch, croscarmellosesodium and carboxymethylcellulose can also be added appropriately.

The solid preparation of the present invention can be produced using theaforementioned essential ingredients and optional ingredients (thosehaving a role as an excipient are included in these ingredients) by theknown method, and can be formulated into, for example, powders,granules, subtle granules, capsules and tablets.

The powders, the granules and the subtle granules can be produced by awet granulation method comprising a step of dissolving or suspending theeffective ingredient in water or a pharmacologically acceptable solventand adding the solution to the sugar or the sugar alcohol. The tabletscan be produced by mixing an appropriate amount of the lubricant such asmagnesium stearate with the aforementioned granulated matter andcompressing and molding this mixture. The capsules can be produced, forexample, by filling the granulated matter in gelatin capsules. In thecases of the above production methods, sodium thiosulfate andhydroxypropylcellulose having the low degree of substitution can beadded in any step. For example, sodium thiosulfate together with theeffective ingredient may be dissolved or suspended in the water or thepharmacologically acceptable solvent, and added to the sugar or thesugar alcohol.

In the wet granulation, an apparatus generally used is used, andexamples thereof may include a fluidized bed granulator, a rotationfluidized bed granulator, a agitating granulator, a cylindricalextruding granulator, and a wet extruding granulator. When the water isused as the solvent for dissolving or suspending the effectiveingredient, the fluidized bed granulator and the rotation fluidized bedgranulator capable of drying with spraying are suitable. When a volatilesolvent such as ethanol as the solvent for dissolving or suspending theeffective ingredient, the fluidized bed granulator, the rotationfluidized bed granulator and the agitating granulator are suitable.

As an apparatus for mixing the preparation, the apparatus generally usedis used, and examples thereof may include a V-shaped mixer, a ribbonmixer, an air blender.

For the compression and molding, the apparatus generally used is used,and may include, for example, a single punch tableting machine, a rotarymode tableting machine. A molding pressure upon tableting is notparticularly limited, and may be the same pressure as in usual tabletsbecause the tablet may have the hardness to such an extent that thehardness is not problematic in handling and the tablet need not beformulated into an orally disintegrating type. Therefore, the pressuremay be set to about 500 to 10,000 kgf/cm² and preferably about 1,500 to5,000 kgf/cm².

The amount of the lubricant to be added is not particularly limited, andfor example, in the case of magnesium stearate, the amount is preferablyabout 0.1 to 5.0% by weight and more preferably about 0.5 to 3.0% byweight per weight of a unit containing the effective ingredient.

The solid preparation comprising the epoxymorphinan derivativerepresented by the general formula (I) or the pharmacologicallyacceptable acid addition salt thereof as the effective ingredient in thepresent invention obtained as described above can be made into a coatingpreparation by adding a coating agent if necessary. The coating agentcan be selected from functional bases depending on a purpose, and thosesuch as hydroxypropylmethylcellulose, polyvinyl alcohol, ethylcellulose,carboxymethylethylcellulose or premix products thereof, which aregenerally commercially available, can be used. The amount of the coatingagent to be added is not particularly limited, and for example, ispreferably 0.1 to 20.0% by weight and more preferably 1 to 10% by weightto weight of a unit containing the effective ingredient that forms acore. Also if necessary, colcothar (iron sesquioxide), yellow colcothar(yellow iron sesquioxide), black iron oxide, titanium oxide and the likemay be added as the coloring agent and a light shielding agent.

For film coating operation, the apparatus generally used is used, and apan coating apparatus is suitable for producing film coating tablets andthe fluidized bed granulator is suitable for film coating granules.

EXAMPLES

The present invention is explained below using Examples in order toclarify excellent effects of the present invention, but the presentinvention is not limited thereto.

Production Example 1 Comparative Example 1

10 Parts by weight (hereinafter abbreviated as a “part,” and the samegoes below unless otherwise specified) of the Compound 1 and 100 partsof crystalline cellulose (Avicel PH-101, Asahi Kasei) were weighed in astandard bottle, 30 parts of distilled water was added, and they weremixed by a glass bar.

Comparative Example 2

The production was performed in the same manner as in ComparativeExample 1, except that crystalline cellulose in Comparative Example 1was replaced with polyvinyl alcohol (PVA EG-5, Nippon Synthetic ChemicalIndustry).

Comparative Example 3

The production was performed in the same manner as in ComparativeExample 1, except that crystalline cellulose in Comparative Example 1was replaced with hydroxypropylcellulose (content of hydroxypropoxylgroup: 53.4 to 77.5%, loose bulk density (apparent specific gravity):0.5 to 0.6 g/mL, viscosity: 6.0 to 10 mPa·s (20° C., 2% aqueoussolution) (HPC-L, Nippon Soda).

Comparative Example 4

The production was performed in the same manner as in ComparativeExample 1, except that crystalline cellulose in Comparative Example 1was replaced with croscarmellose sodium (Ac-di-sol, FMC Bio Polymer)(hereinafter abbreviated as Ac-di-sol).

Comparative Example 5

The production was performed in the same manner as in ComparativeExample 1, except that crystalline cellulose in Comparative Example 1was replaced with carboxymethylcellulose calcium (CMC-Ca, ECG-505,Gotoku Chemical) (hereinafter abbreviated as CMC-Ca).

Comparative Example 6

A solid preparation was produced according to the technique described inInternational Publication WO99/02158 Pamphlet (Patent Document 2). 49.91Parts of lactose (Pharmatose 200M, DMV) and 26.4 parts of crystallinecellulose (Avicel PH-101, Asahi Kasei) were weighed, and placed in afluidized bed granulator (FLO-5, Freund Corporation). A spray solutionin which 0.01 part of the Compound 1, 0.08 part of sodium thiosulfatehydrate (Kokusan Chemical) and 3.2 parts of hydroxypropylcellulose(content of hydroxypropoxyl group: 53.4 to 77.5%, loose bulk density(apparent specific gravity): 0.5 to 0.6 g/mL, viscosity: 3.0 to 5.9mPa·s (20° C., 2% aqueous solution) (HPC-SL, Nippon Soda) had beendissolved in distilled water was sprayed to the obtained granulatedgranules (average particle diameter of 95 μm when measured according tothe particle size measurement method in the 15th revised JapanesePharmacopoeia) to produce granulated granules. The granulated granuleswere treated using a comil (197S, Powrex) to obtain uniformly sizedgranules. 0.4 Part of magnesium stearate (Taihei Chemical Industrial)was added to 79.6 parts of the uniformly sized granules, and they weremixed for 5 minutes. The obtained granules were made into a tablet of 80mg using a tableting machine (correct 19, Kikusui Seisakusho).

Example 1

78.895 Parts of mannitol (Pearitol SD200, Roquette Japan) was weighedand placed into the fluidized bed granulator (FLO-5, Freund Corporation)after passing through a sieve with mesh having an opening of 1 mm. Aspray solution in which 0.005 part of the Compound 1 and 0.1 part ofsodium thiosulfate hydrate had been dissolved in distilled water wassprayed to the obtained granulated granules (average particle diameterof 146 μm when measured according to the particle size measurementmethod in the 15th revised Japanese Pharmacopoeia) to producedrug-carrying granules. 15 Parts of mannitol and 5 parts ofhydroxypropylcellulose having a low degree of substitution (averageparticle diameter: 50 μm, content of hydroxypropoxyl group: 10.0 to12.9% by weight, loose bulk density: 0.34 g/mL, LH11, Shin-EtsuChemical) (hereinafter abbreviated as L-HPC) were added to 79 parts ofthe drug-carrying granules, and they were mixed for 15 minutes using aV-shaped mixer (permeation mode S-5, Tsutsui Scientific Instruments).Further 1 part of magnesium stearate (Taipei Chemical Industrial) wasadded, and they were mixed for 5 minutes. The obtained granules weremade into a tablet of 100 mg using the tableting machine (correct 19,Kikusui Seisakusho).

Example 2

Drug-carrying granules were produced in the same manner as in Example 1,and a tablet was made by mixing and tableting in the same manner as inExample 1, except that 10 parts of mannitol, 10 parts of L-HPC and 1part of magnesium stearate were added to 79 parts of the Compound1-carrying granules.

Example 3

Drug-carrying granules were produced in the same manner as in Example 1,and a tablet was made by mixing and tableting in the same manner as inExample 1, except that 20 parts of L-HPC and 1 part of magnesiumstearate were added to 79 parts of the Compound 1-carrying granules.

Comparative Example 7

Drug-carrying granules were produced in the same manner as in Example 1,and a tablet was made by mixing and tableting in the same manner as inExample 1, except that 15 parts of mannitol, 5 parts of Ac-di-sol inplace of L-HPC and 1 part of magnesium stearate were added to 79 partsof the Compound 1-carrying granules.

Comparative Example 8

Drug-carrying granules were produced in the same manner as in Example 1,and a tablet was made by mixing and tableting in the same manner as inExample 1, except that 10 parts of mannitol, 10 parts of CMC-Ca in placeof L-HPC and 1 part of magnesium stearate were added to 79 parts of theCompound 1-carrying granules.

Example 4

68.895 Parts of mannitol (Pearitol SD200, Roquette Japan) was weighedand placed into a mortar after passing through the sieve with meshhaving the opening of 1 mm. As a spray solution in which 0.005 part ofthe Compound 1 and 0.1 part of sodium thiosulfate hydrate had beendissolved in distilled water was sprayed, they were mixed for 5 minutes.The mixture was dried at 45° C. for 2 hours using a hot wind dryer(PS-212, ESPEC). A particle size was sorted using the comil (197S,Powrex), 30 parts of L-HPC was added, and they were mixed for 15 minutesusing the V-shaped mixer (permeation mode S-5, Tsutsui ScientificInstruments). Further 1 part of magnesium stearate (Taihei ChemicalIndustrial) was added, and they were mixed for 5 minutes. The obtainedgranules were made into a tablet of 100 mg using the tableting machine(Correct 19, Kikusui Seisakusho).

Example 5

88.895 Parts of erythritol (Nikken Chemical Synthetic Industry) wasweighed and placed into the mortar after passing through the sieve withmesh having the opening of 1 mm. As a spray solution in which 0.005 partof the Compound 1 and 0.1 part of sodium thiosulfate hydrate had beendissolved in distilled water was sprayed, they were mixed for about 5minutes. The mixture was dried at 45° C. for 2 hours using the hot winddryer (PS-212, ESPEC). A particle size was sorted using the comil (197S,Powrex), 10 parts of L-HPC was added, and they were mixed for 15 minutesusing the V-shaped mixer (permeation mode S-5, Tsutsui ScientificInstruments). Further 1 part of magnesium stearate (Taipei ChemicalIndustrial) was added, and they were mixed for 5 minutes. The obtainedgranules were made into a tablet of 100 mg using the tableting machine(Correct 19, Kikusui Seisakusho).

Example 6

Granules were obtained by producing in the same manner as in Example 5,except that erythritol in Example 5 was replaced with potato starch(ST-P, Nippon Starch Chemical).

Example 7

A tablet was produced in the same manner as in Example 5, except thaterythritol in Example 5 was replaced with maltitol (powder maltitol G-3,Towa Kasei).

Example 8

A tablet was produced in the same manner as in Example 5, except thaterythritol in Example 5 was replaced with saccharose (Suzu FunmatsuYakuhin).

Comparative Example 9

A tablet was produced in the same manner as in Example 4, except thatthe amount of blended mannitol was 58.895 parts and the amount ofblended L-HPC was 40 parts.

Example 9

A tablet was produced in the same manner as in Example 5, except thaterythritol in Example 5 was replaced with mannitol (Pearitol SD200,Roquette Japan).

Comparative Example 10

A tablet was produced in the same manner as in Example 5, except thaterythritol in Example 5 was replaced with mannitol (Pearitol SD200,Roquette Japan) and sodium thiosulfate hydrate was not added.

Example 10

122.005 Parts of lactose (Lactose 200M, DMV), 4.2 parts ofhydroxypropylcellulose (HPC-SL, Nippon Soda) and 12.25 parts of L-HPCwere placed in a agitating mixing granulator (FM-VG-10P, Powrex), andmixed. Subsequently, a spray solution in which 0.005 part of theCompound 1 and 0.14 part of sodium thiosulfate hydrate had beendissolved in purified water was sprayed thereto to produce drug-carryinggranules. After passing the granules through the sieve with mesh havingthe opening of 0.7 mm, 1.4 parts of magnesium stearate was added andmixed. The obtained granules were made into a tablet of 140 mg using thetableting machine (VIRGO 0512SS2AZ, Kikusui Seisakusho).

Examples 11 and 12

Tablets were obtained by mixing and tableting in the same manner as inExample 10, except that the amounts of blended lactose and L-HPC werechanged to the amounts in Table 4.

Comparative Example 11

A tablet was obtained by mixing and tableting in the same manner as inExample 10, except that the amounts of blended lactose and L-HPC werechanged to the amounts in Table 4.

(Storage Stability Test)

A stability was evaluated by measuring a residual ratio (%) of the drugusing an HPLC method after the compositions, granules or tabletsobtained in Comparative Examples 1 to 9 and 11 and Examples 1 to 8 and10 to 12 were left to stand in an open state under a condition at 40°C./75% RH which was an acceleration condition described in Drug Approvaland Licensing Procedure in Japan (2006) (Tables 1, 2 and 4). Thestability of the tables in Example 9 and Comparative Example 10 wasevaluated by measuring the amount (%) of the degraded drug after beingleft to stand in the open state under a condition at 60° C./75% RH thatwas a stress condition (Table 3).

TABLE 1 The list of the formulations and the results of storagestability test (Comparative Examples) Comparative Examples Formulatedingredients 1 2 3 4 5 6 7 8 9 Compound 1 9.1 9.1 9.1 9.1 9.1 0.01250.005 0.005 0.005 Mannitol — — — — — — 93.895 88.895 58.895 Lactose — —— — — 62.3875 — — — Crystalline cellulose 90.9 — — — — 33 — — — L-HPC —— — — — — — — 40 PVA — 90.9 — — — — — — — Hydroxypropylcellulose — —90.9 — — 4 — — — Ac-di-sol — — — 90.9 — — 5 — — CMC-Ca — — — — 90.9 — —10 — Sodium thiosulfate hydrate — — — — — 0.1 0.1 0.1 0.1 Magnesiumstearate — — — — — 0.5 1 1 1 Total 100 100 100 100 100 100 100 100 100Residual ratio (%) of the drug 093.0% 87.1% 92.2% 93.7% 90.2% — — — —after being left to stand in an open state under a condition at 40°C./75% RH for two weeks Residual ratio (%) of the drug — — — — — 94.4%93.7% 93.0% 96.8% after being left to stand in an open state under acondition at 40° C./75% RH for one month Blended unit of formulatedingredient: indicated by percent by weight to weight of a unit of thepreparation

TABLE 2 The list of the formulations and the results of storagestability test (Examples) Examples Formulated ingredients 1 2 3 4 5 6 78 Compound 1 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 Mannitol93.895 88.895 78.895 68.895 — — — — Erythritol — — — — 88.895 — — —Starch — — — — — 88.895 — — Maltitol — — — — — — 88.895 — Saccharose — —— — — — — 88.895 L-HPC 5 10 20 30 10 10 10 10 Sodium thiosulfate hydrate0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Magnesium stearate 1 1 1 1 1 1 1 1 Total100 100 100 100 100 100 100 100 Residual ratio (%) of the 97.9% 98.3%98.2% 100.3% 99.4% 102.9% 99.0% 99.3% compound after being left to standin an open state under a condition at 40° C./75% RH for one monthBlended unit of formulated ingredient: indicated by percent by weight toweight of a unit of the preparation

TABLE 3 The list of the formulations and the results of storagestability test Comparative Formulated ingredients Example 9 Example 10Compound 1 0.005 0.005 Mannitol 88.895 88.995 L-HPC 10 10 Sodiumthiosulfate hydrate 0.1 — Magnesium stearate 1 1 Total 100 100 Amount ofproduced major degradation N.D. 0.67% product (N-oxide) after thecompound is (<0.05%) left to stand in an open state under a condition at60° C./75% RH for ten days Blended unit of formulated ingredient:indicated by percent by weight to weight of a unit of the preparation

TABLE 4 The list of the formulations and the results of storagestability test Comparative Formulated ingredients Example 10 Example 11Example 12 Example 11 Compound 1 0.0036 0.0036 0.0036 0.0036 Lactose87.1464 78.3964 65.8964 55.8964 Hydroxypropylcellulose 3 3 3 3 L-HPC8.75 17.5 30.0 40.0 Sodium thiosulfate hydrate 0.1 0.1 0.1 01 Magnesiumstearate 1 1 1 1 Total 100.0 100.0 100.0 100.0 Residual ratio (%) of the97.6% 98.8% 98.8% 96.8% compound after being left to stand in an openstate under a condition at 40° C./75% RH for one month Blended unit offormulated ingredient: indicated by percent by weight to weight of aunit of the preparation

As shown in Tables 1, 2 and 4, any of the solid preparations containingsodium thiosulfate, the sugar or the sugar alcohol, andhydroxypropylcellulose having the low degree of substitution in theamount of 1 to 30% by weight per weight of a unit containing theeffective ingredient exhibited the residual ratio of 97% or more evenwhen stored without being packed under the condition at 40° C./75% RHfor one month, exhibited the remarkable stabilization effect comparedwith the formulations in Comparative Examples, and was shown to be ableto assure the sufficient stability upon handling pharmaceuticals. Asshown in Table 3, no degraded product was detected in the solidpreparation containing the sugar or sugar alcohol andhydroxypropylcellulose having the low degree of substitution in theamount of 1 to 30% by weight per weight of a unit containing theeffective ingredient, even when the solid preparation was stored underthe condition at 60° C./75% RH for 10 days. Thus, it was elucidated thatsodium thiosulfate was the essential ingredient for assuring thesufficient stability during the production and the storage.

Production Example 2 Example 13

71.095 Parts of mannitol (Pearitol SD200, Roquette Japan) was weighedand placed into the fluidized bed granulator (FLO-5, Freund Corporation)after passing through the sieve with mesh having the opening of 1 mm. Aspray solution in which 0.005 part of the Compound 1 and 0.1 part ofsodium thiosulfate hydrate (Kokusan Chemical) had been dissolved indistilled water was sprayed thereto to produce drug-carrying granules.Subsequently, 8 parts of L-HPC (LH-11, Shin-Etsu Chemical) was added to71.2 parts of the drug-carrying granules, and they were mixed for 15minutes using the V-shaped mixer (permeation mode S-5, TsutsuiScientific Instruments). Further 0.8 part of magnesium stearate (TaiheiChemical Industrial) was added, and they were mixed for 5 minutes. Theobtained granules were made into a tablet of 80 mg using the tabletingmachine (correct 19, Kikusui Seisakusho). Subsequently, this tablet wasplaced in a film coating machine (High Coater Mini, Freund Corporation),and a solution in which OPADRY OY-7300 (Colorcon Japan) and ironsesquioxide (Kishi Kasei) had been dissolved or dispersed was sprayed toproduce a coating tablet of 84 mg in which 4 mg of the coating agent wasadded to the tablet of 80 mg.

Example 14

71.0975 Parts of mannitol (Pearitol SD200, Roquette Japan) was weighedand placed into the fluidized bed granulator (FLO-5, Freund Corporation)after passing through the sieve with mesh having the opening of 1 mm. Aspray solution in which 0.0025 part of the Compound 1 and 0.1 part ofsodium thiosulfate hydrate (Kokusan Chemical) had been dissolved indistilled water was sprayed thereto to produce drug-carrying granules.Subsequently, 8 parts of L-HPC (LH-11, Shin-Etsu Chemical) was added to71.2 parts of the drug-carrying granules, and they were mixed for 15minutes using the V-shaped mixer (permeation mode S-5, TsutsuiScientific Instruments). Further 0.8 part of magnesium stearate (TaiheiChemical Industrial) was added, and they were mixed for 5 minutes. Theobtained granules were made into a tablet of 80 mg using the tabletingmachine (correct 19, Kikusui Seisakusho). Subsequently, this tablet wasplaced in the film coating machine (High Coater Mini, FreundCorporation), and a solution in which OPADRY OY-7300 (Colorcon Japan),iron sesquioxide (Kishi Kasei) and black iron oxide (Kishi Kasei) hadbeen dissolved or dispersed was sprayed to produce a coating tablet of84 mg in which 4 mg of the coating agent was added to the tablet of 80mg.

Example 15

71.095 Parts of mannitol (Pearitol SD200, Roquette Japan) was weighedand placed into the fluidized bed granulator (FLO-5, Freund Corporation)after passing through the sieve with mesh having the opening of 1 mm. Aspray solution in which 0.005 part of the Compound 1 and 0.1 part ofsodium thiosulfate hydrate (Kokusan Chemical) had been dissolved indistilled water was sprayed thereto to produce drug-carrying granules.Subsequently, 8 parts of L-HPC (LH-11, Shin-Etsu Chemical) was added to71.2 parts of the drug-carrying granules, and they were mixed for 15minutes using the V-shaped mixer (permeation mode S-5, TsutsuiScientific Instruments). Further 0.8 part of magnesium stearate (TaiheiChemical Industrial) was added, and they were mixed for 5 minutes. Theobtained granules were made into a tablet of 80 mg using the tabletingmachine (Correct 19, Kikusui Seisakusho). Subsequently, this tablet wasplaced in the film coating machine (High Coater Mini, FreundCorporation), and a solution in which OPADRY 11 HP (Colorcon Japan) andiron sesquioxide (Kishi Kasei) had been dissolved or dispersed wassprayed thereto to produce a coating tablet of 84 mg in which 4 mg ofthe coating agent was added to the tablet of 80 mg.

Example 16

109.7575 Parts of lactose (Lactose 200M, DMV), 4.2 parts ofhydroxypropylcellulose (HPC-SL, Nippon Soda) and 24.5 parts of L-HPC(LH-31, Shin-Etsu Chemical) were placed in the agitating mixinggranulator (FM-VG-10P, Powrex), and mixed. Subsequently, a spraysolution in which 0.0025 part of the Compound 1 and 0.14 part of sodiumthiosulfate hydrate had been dissolved in purified water was sprayedthereto to produce drug-carrying granules. After passing the granulesthrough the sieve with mesh having the opening of 0.7 mm, 1.4 parts ofmagnesium stearate was added and mixed. The obtained granules were madeinto a tablet of 140 mg using the tableting machine (VIRGO 0512SS2AZ,Kikusui Seisakusho). Subsequently, this tablet was placed in a filmcoating machine (High Coater, Freund Corporation), and then a solutionin which hydroxypropylmethylcellulose (TC-5, Shin-Etsu Chemical), ironsesquioxide (Kishi Kasei) and titanium oxide (Ishihara Sangyo) had beendissolved or dispersed was sprayed to produce a coating tablet of 147 mgin which 7 mg of the coating agent was added to the tablet of 140 mg.

Example 17

A tablet was produced in the same manner as in Example 16, except thatthe amount of the blended Compound 1 was 0.005 part and the amount ofblended lactose was 109.755 parts.

(Storage Stability Test)

The stability was evaluated by measuring the residual ratio (%) of thedrug using the HPLC method after the film coating tablets obtained inExamples 13 to 17 was left to stand in the open state under thecondition at 40° C./75% RH that was the acceleration condition describedin Drug Approval and Licensing Procedure in Japan (2006) (Table 5).

TABLE 5 The list of the formulations and the results of storagestability test Formulated ingredients Example 13 Example 14 Example 15Example 16 Example 17 Compound 1 0.005 0.0025 0.005 0.0025 0.005Mannitol 71.095 71.095 71.095 — — Lactose — — — 109.7575 109.755Hydroxypropylcellulose — — — 4.2 4.2 L-HPC 8 8 8 24.5 24.5 Sodiumthiosulfate hydrate 0.1 0.1 0.1 0.14 0.14 Magnesium stearate 0.8 0.8 0.81.4 1.4 Film coating 4 4 4 7 7 Total 84 84 84 147 147 Base for filmcoating OPADRY OPADRY OPADRY II Hydroxypropyl- Hydroxypropyl- OY-7300OY-7300 HP methylcellulose methylcellulose Added dye iron sesquioxideiron sesquioxide iron sesquioxide titanium oxide titanium oxide blackiron oxide iron sesquioxide iron sesquioxide Residual ratio (%) of the99.4% 99.1% 98.3% 98.8% 99.5% compound after being left to stand in anopen state under a condition at 40° C./75% RH for one month It isindicated by blended amount (mg) of the formulated ingredient

As shown in Table 5, any of the film coating tablets shown in Examples13 to 17 containing sodium thiosulfate, the sugar or the sugar alcohol,and hydroxypropylcellulose having the low degree of substitution in theamount of 1 to 30% by weight per weight of a unit containing theeffective ingredient exhibited the residual ratio of 97% or more evenwhen stored without being packed under the condition at 40° C./75% RHfor one month, and was shown to be able to assure the sufficientstability upon handling pharmaceuticals.

The invention claimed is:
 1. A stable solid preparation comprising as an effective ingredient a 4,5-epoxymorphinan derivative represented by the general formula (I):

wherein in formula (I) a double line of a dashed line and a solid line represents a double bond or a single bond; R¹ represents alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, Amyl having 4 to 7 carbon atoms, allyl, furan-2-ylalkyl having 1 to 5 carbon atoms or thiophene-2-ylalkyl having 1 to 5 carbon atoms; R² represents hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms or —NR⁷R⁸; R⁷ represents hydrogen or alkyl having 1 to 5 carbon atoms; R⁸ represents hydrogen, alkyl having 1 to 5 carbon atoms or C(═O)R⁹; R⁹ represents hydrogen, phenyl or alkyl having 1 to 5 carbon atoms; R³ represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms or alkoxy having 1 to 5 carbon atoms; A represents —N(R⁴)C(═X)Y—, —N(R⁴)C(═X)Y—, —N(R⁴)—, or —N(R⁴)SO₂—, wherein X and Y each independently represents NR⁴, S or O, and R⁴ represents hydrogen, straight or branched alkyl having 1 to 5 carbon atoms or aryl having 6 to 12 carbon atoms, and R⁴ is the same or different; B represents (i) a valence bond, (ii) straight or branched alkylene having 1 to 14 carbon atoms, which is optionally substituted with at least one or more substituents selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and phenoxy, wherein 1 to 3 methylene groups in the alkylene (ii) is optionally replaced with carbonyl groups, (iii) straight or branched non-cyclic unsaturated hydrocarbon containing 1 to 3 double bonds and/or triple bonds and having 2 to 14 carbon atoms, which is optionally substituted with at least one or more substituents selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy and phenoxy, wherein 1 to 3 methylene groups in the hydrocarbon (iii) is optionally replaced with carbonyl groups, or (iv) straight or branched saturated or unsaturated hydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or amino bonds and having 1 to 14 carbon atoms, wherein the heteroatom in the hydrocarbon (iv) is not directly bound to A, and 1 to 3 methylene groups in the hydrocarbon (iv) is optionally replaced with carbonyl groups; R⁵ represents hydrogen or an organic group having the following basic skeleton:

wherein the organic group is optionally substituted with one or more substituents selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanate, trifluoromethyl, trifluoromethoxy and methylenedioxy; and R⁶ represents hydrogen, alkyl having 1 to 5 carbon atoms or alkanoyl having to 5 carbon atoms; or a pharmacologically acceptable acid addition salt thereof; and further comprising sodium thiosulfate, a sugar or a sugar alcohol, and hydroxypropylcellulose having a low degree of substitution in an amount of 1 to 30% by weight per weight of a unit containing the effective ingredient.
 2. The stable solid preparation according to claim 1, wherein said sugar or sugar alcohol contains at least one selected from the group consisting of starch, saccharose, lactose, mannitol, erythritol and maltitol.
 3. The stable solid preparation according to claim 1, wherein said sugar or sugar alcohol is a granulated granule manufactured by extruding granulation, agitating granulation, spray drying or fluidized bed granulation.
 4. The stable solid preparation according to claim 1, which is obtained by a production method comprising a step of dissolving or suspending the effective ingredient in water or a pharmacologically acceptable solvent to produce a solution or suspension, and a step of adding the solution or suspension to the sugar or the sugar alcohol.
 5. The stable solid preparation according to claim 1, which is a tablet, a capsule, a granule, a subtle granule or a powder.
 6. The solid preparation according to claim 1, wherein said solid preparation is coated.
 7. The stable solid preparation according to claim 1, wherein the hydroxypropylcellulose having a low degree of substitution has a hydroxypropoxyl content of 10.0% by weight to 12.9% by weight. 